cis-[PtCl2(4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine)2]: a sterically restrictive new cisplatin analogue. Reaction kinetics with model nucleobases, DNA interaction studies, antitumor activity, and structure-activity relationships.
The formation and isolation of the antitumor drug cisplatin analogue cis-[PtCl2(Hmtpo-N3)2].2H2O (1) (where Hmtpo = 4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine) by reaction of Hmpto with K2[PtCl4] in HCl (0.5 N) is reported. This complex crystallizes in the monoclinic space group P21/c with unit cell dimensions a = 15.215(2) A, b = 9.629(1) A, c = 13.115(3) A, beta = 97.40(2) degrees, and Z = 4. The molecular structure shows that Pt is in an almost square planar environment, PtN2Cl2, which has a cis configuration. The Hmpto ligands show a head to head orientation in the solid state and nonrestricted rotation about the Pt-N bonds in solution. The reactivity of the complex to model nucleobases 9-ethylguanine (9-EtGH) and 1-methylcytosine (1-MeC) has been investigated by 1H NMR spectroscopy at 45 degrees C in aqueous media. The results show that 1 reacts slowly with 9-EtGH (t1/2 approximately 5 days) by displacement of Cl-, producing cis-[Pt(mtpo-N3)2(9-EtGH-N7)2], which is similar to the major cross-link adduct of cisplatin with DNA. However, 1 gives no reaction with 1-MeC. This appears to be due to the lesser reactivity of 1-MeC and to competition between the cross-link reaction and dimerization of 1 to [Pt2(mu-mtpo-N3,N4)4]. Circular dichroism studies of DNA in the presence of 1 show that the platinum complex reacts efficiently after 48 h at a optimum ratio of 0.25 Pt atom/mol of DNA nucleotide. These results and those obtained from reaction of 1 with 9-EtGH suggest that the platinum compound binds the N7 atoms of two guanines of the same strand, forming intrastrand cross-linked adducts. Chelation of DNA bases by 1 causes important conformational changes, bringing the guanines close together. The anticancer activity of complex 1 has been tested against the human cancer cell lines MCF-7 breast carcinoma and A121 ovarian carcinoma. Results indicate a moderate antitumor activity against breast carcinoma and a marked and selective cytotoxic effect against ovarian carcinoma.
Navarro
J A
JA
Departamento de Química Inorgánica, Universidad de Granada, Spain.
Salas
J M
JM
Romero
M A
MA
Vilaplana
R
R
Gonzalez-Vílchez
F
F
Faure
R
R
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C110509:(PtCl2(4,7-H-5-methyl-7-oxo(1,2,4)triazolo(1,5-a)pyrimidine)2); D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D004247:DNA; D002945:Cisplatin